Background
Reported odds ratios and population attributable fractions (PAF) for late-onset Alzheimer’s disease (LOAD) risk loci (BIN1, ABCA7, CR1, MS4A4E, CD2AP, PICALM, MS4A6A, CD33, and CLU) come from clinically ascertained samples. Little is known about the combined PAF for these LOAD risk alleles and the utility of these combined markers for case-control prediction. Here we evaluate these loci in a large population-based sample to estimate PAF and explore the effects of additive and non-additive interactions on LOAD status prediction performance.
Methods
2,419 samples from the Cache County Memory Study were genotyped for APOE and nine LOAD risk loci from AlzGene.org. We used logistic regression and ROC analysis to assess the LOAD status prediction performance of these loci using additive and non-additive models, and compared ORs and PAFs between AlzGene.org and Cache County.
Results
Odds ratios were comparable between Cache County and AlzGene.org when identical SNPs were genotyped. PAFs from AlzGene.org ranged from 2.25–37%; those from Cache County ranged from 0.05–20%. Including non-APOE alleles significantly improved LOAD status prediction performance (AUC = 0.80) over APOE alone (AUC = 0.78) when not constrained to an additive relationship (p < 0.03). We identified potential allelic interactions (p-values uncorrected): CD33-MS4A4E (Synergy Factor = 5.31; p < 0.003) and CLU-MS4A4E (SF = 3.81; p < 0.016).
Conclusions
While non-additive interactions between loci significantly improve diagnostic ability, the improvement does not reach the desired sensitivity or specificity for clinical use. Nevertheless, these results suggest that understanding gene-gene interactions may be important in resolving Alzheimer’s disease etiology.